T-cell immunity is known to wane with old age, and this defect is likely to impair protection against primary infection with a wide variety of pathogens. New results from the Nikolich lab strongly suggest that defects in effector T-cell differentiation underlie the age-related susceptibility to the West Nile virus (WNV). Moreover, preliminary results suggest that similar defects may exist in old mice infected with vaccinia virus (VACV). While much remains to be learned about the basic biology of this defect(s), its phenotypic manifestation is the reduced expression of the key effector molecules of the lytic pathway (Perforin/Granzyme B) and IFNy. Dr. Nikolich has made numerous important contributions to the biology of CDS T-cells in adult and aged organisms in the context of immunity and infection, and will deploy his knowledge and leadership skills to lead this Project and the entire P01. Aims are : (i) to investigate the mechanistic features and the breadth of the putative common T-cell defect(s) that underlie age-related susceptibility to different bioattack agents (by broadening the studies to Listeria, monkeypox and Francisella models); (ii) to examine whether therapy of effector T-cell maturation can be achieved by correcting lytic complex and IFNy defects and whether such intervention can restore protective immunity to old mice. In collaboration with Projects 1.1, 1.2 & 1.3, we shall then synthesize the results and knowledge to select the most efficient treatment(s); and (iii) to test in aged monkeys he most efficacious treatment validated in rodents, using the monkeypox virus model.